PROJECTSUMMARY Inrecentyears,immunotherapieshavetransformedthetreatmentlandscapeforpatientswithadvancedlung cancer and melanoma, leading to durable responses in a subset of cases but rarely curing patients of the disease.Thesetreatments,inparticular,immunecheckpointinhibitors(ICIs)thatblockinhibitorysignalsonT- cells,likeprogrammedcelldeathprotein1(PD-1),leadtoresponsesin15-20%ofunselectedpatientswithnon- small cell lung cancer (NSCLC) and up to 60% of melanoma patients. On the basis of these studies several immunecheckpointinhibitorshavebeenFDA-approvedforthetreatmentofmetastaticmelanomaandadvanced NSCLC.Increasingnumbersofpatientsarereceivingthesetherapies,howevermanyinitiallybenefitfromthem and eventually develop drug-resistant disease. To date, there is little knowledge of the molecular and cellular mechanismsthatunderlieacquiredresistancetoICIs.Asaresult,effectivetherapeuticstrategiestotreatpatients withICI-resistantdiseasearelacking.Thelong-termgoaloftheresearchproposedhereistoprovidemechanistic insightintoacquiredresistancetoICIsinlungcancerandmelanomaandthuscontributetothedevelopmentof evidence-basedapproachestoovercomeICIresistance. Our group has pioneered approaches to study mechanisms of acquired resistance to ICIs in lung cancer. Moreover, we have optimized methods for the in vivo analysis of resistance to ICIs in immunocompetent lung cancerandmelanomamousemodels.ThesestudieshaverevealedthatimpairedMHCIantigenpresentation playsacentralroleinconferringacquiredresistancetoICIs.Wehypothesizethatmultipledifferentmechanisms including genetic alterations, epigenetic changes and altered immune signaling pathways can lead to downregulation of antigen presentation causing resistance to ICIs. Further, we posit that knowledge of these mechanismsandtheirimmunologicalconsequencescanbeusedtodevisetherapeuticstrategiestoovercome ICI-resistance.Thus,weproposetoleverageouruniqueexperimentalsystemsto:1)Determinehowdefectsin MHC I antigen presentation in ICI-resistant tumors affect the immune landscape, especially natural killer (NK) cellfunction,2)ElucidatethegeneticprocessesthatleadtoimpairedMHCIantigenpresentationinICI-resistant lung cancers and 3) Determine whether epigenetic silencing of genes encoding MHC I APM components can lead to resistance to ICIs. Together, these studies will provide us with a comprehensive understanding of the mechanisms that underlie defects in MHC I antigen presentation in lung tumors and melanomas resistant to immunecheckpointinhibitorsandwillsetthestageforpotentialnewapproachestoovercomethisresistance.